Adjusting for treatment switching in the METRIC study shows further improved overall survival with trametinib compared with chemotherapy

Trametinib, a selective inhibitor of mitogen-activated protein kinase kinase 1 (MEK1) and MEK2, significantly improves progression-free survival compared with chemotherapy in patients with BRAF V600E/K mutation–positive advanced or metastatic melanoma (MM). However, the pivotal clinical trial permitted randomized chemotherapy control group patients to switch to trametinib after disease progression, which confounded estimates of the overall survival (OS) advantage of trametinib. Our purpose was to estimate the switching-adjusted treatment effect of trametinib for OS and assess the suitability of each adjustment method in the primary efficacy population. Of the patients randomized to chemotherapy, 67.4% switched to trametinib. We applied the rank-preserving structural failure time model, inverse probability of censoring weights, and a two-stage accelerated failure time model to obtain estimates of the relative treatment effect adjusted for switching. The intent-to-treat (ITT) analysis estimated a 28% reduction in the hazard of death with trametinib treatment (hazard ratio [HR], 0.72; 95% CI, 0.52–0.98) for patients in the primary efficacy population (data cut May 20, 2013). Adjustment analyses deemed plausible provided OS HR point estimates ranging from 0.48 to 0.53. Similar reductions in the HR were estimated for the first-line metastatic subgroup. Treatment with trametinib, compared with chemotherapy, significantly reduced the risk of death and risk of disease progression in patients with BRAF V600E/K mutation–positive advanced melanoma or MM. Adjusting for switching resulted in lower HRs than those obtained from standard ITT analyses. However, CI are wide and results are sensitive to the assumptions associated with each adjustment method

Vacuum-UV negative photoion spectroscopy of CH3F, CH3Cl and CH3Br

Using tunable vacuum-UV radiation from a synchrotron, negative ions are detected by quadrupolar mass spectrometry following photoexcitation of three gaseous halogenated methanes CH$_3$X (X = F,Cl,Br). The anions X$^-$, H$^-$, CX$^-$, CHX$^-$ and CH$_2$X$^-$ are observed, and their ion yields recorded in the range 8-35 eV. The anions show a linear dependence of signal with pressure, showing that they arise from unimolecular ion-pair dissociation, generically described as AB + h$v$ $\rightarrow$ A$^-$ + B$^+$ (+ neutrals). Absolute cross sections for ion-pair formation are obtained by calibrating the signal intensities with those of F$^-$ from both SF$_6$ and CF$_4$. The cross sections for formation of X$^-$ + CH$_3$$^+$ are much greater than for formation of CH$_2$X$^-$ + H$^+$. In common with many quadrupoles, the spectra of $m$/$z$ 1 (H$^-$) anions show contributions from all anions, and only for CH$_3$Br is it possible to perform the necessary subtraction to obtain the true H$^-$ spectrum. The anion cross sections are normalised to vacuum-UV absorption cross sections to obtain quantum yields for their production. The appearance energies of X$^-$ and CH$_2$X$^-$ are used to calculate upper limits to 298 K bond dissociation energies for D$^o$ (H$_3$C-X) and D$^o$ (XH$_2$C-H) which are consistent with literature values. The spectra suggest that most of the anions are formed indirectly by crossing of Rydberg states of the parent molecule onto an ion-pair continuum. The one exception is the lowest-energy peak of F$^-$ from CH$_3$F at 13.4 eV, where its width and lack of structure suggest it may correspond to a direct ion-pair transition

Realization of Artificial Ice Systems for Magnetic Vortices in a Superconducting MoGe Thin-film with Patterned Nanostructures

We report an anomalous matching effect in MoGe thin films containing pairs of circular holes arranged in such a way that four of those pairs meet at each vertex point of a square lattice. A remarkably pronounced fractional matching was observed in the magnetic field dependences of both the resistance and the critical current. At the half matching field the critical current can be even higher than that at zero field. This has never been observed before for vortices in superconductors with pinning arrays. Numerical simulations within the nonlinear Ginzburg-Landau theory reveal a square vortex ice configuration in the ground state at the half matching field and demonstrate similar characteristic features in the field dependence of the critical current, confirming the experimental realization of an artificial ice system for vortices for the first time.Comment: To appear in Phys. Rev. Let

Calculating error bars for neutrino mixing parameters

One goal of contemporary particle physics is to determine the mixing angles and mass-squared differences that constitute the phenomenological constants that describe neutrino oscillations. Of great interest are not only the best fit values of these constants but also their errors. Some of the neutrino oscillation data is statistically poor and cannot be treated by normal (Gaussian) statistics. To extract confidence intervals when the statistics are not normal, one should not utilize the value for chisquare versus confidence level taken from normal statistics. Instead, we propose that one should use the normalized likelihood function as a probability distribution; the relationship between the correct chisquare and a given confidence level can be computed by integrating over the likelihood function. This allows for a definition of confidence level independent of the functional form of the !2 function; it is particularly useful for cases in which the minimum of the !2 function is near a boundary. We present two pedagogic examples and find that the proposed method yields confidence intervals that can differ significantly from those obtained by using the value of chisquare from normal statistics. For example, we find that for the first data release of the T2K experiment the probability that chisquare is not zero, as defined by the maximum confidence level at which the value of zero is not allowed, is 92%. Using the value of chisquare at zero and assigning a confidence level from normal statistics, a common practice, gives the over estimation of 99.5%.Comment: 9 pages, 6 figure

Neutrino oscillations: measuring θ13\theta_{13} including its sign

In neutrino phenomenology, terms in the oscillation probabilities linear in $\sin \theta_{13}$ lead naturally to the question ``How can one measure $\theta_{13}$ including its sign?'' Here we demonstrate analytically and with a simulation of neutrino data that ${\mathcal P}_{e\mu}$ and {\mathcal {P}_{\mu\mu} at $L/E = 2\pi/\Delta_{21}$ exhibit significant linear dependence on $\theta_{13}$ in the limit of vacuum oscillations. Measurements at this particular value of $L/E$ can thus determine not only $\theta_{13}$ but also its sign, if CP violation is small.Comment: 5 pages, 5 figure

Spatial adaptivity of the SAAF and Weighted Least Squares (WLS) forms of the neutron transport equation using constraint based, locally refined, isogeometric analysis (IGA) with dual weighted residual (DWR) error measures

This paper describes a methodology that enables NURBS (Non-Uniform Rational B-spline) based Isogeometric Analysis (IGA) to be locally refined. The methodology is applied to continuous Bubnov-Galerkin IGA spatial discretisations of second-order forms of the neutron transport equation. In particular this paper focuses on the self-adjoint angular flux (SAAF) and weighted least squares (WLS) equations. Local refinement is achieved by constraining degrees of freedom on interfaces between NURBS patches that have different levels of spatial refinement. In order to effectively utilise constraint based local refinement, adaptive mesh refinement (AMR) algorithms driven by a heuristic error measure or forward error indicator (FEI) and a dual weighted residual (DWR) or goal-based error measure (WEI) are derived. These utilise projection operators between different NURBS meshes to reduce the amount of computational effort required to calculate the error indicators. In order to apply the WEI to the SAAF and WLS second-order forms of the neutron transport equation the adjoint of these equations are required. The physical adjoint formulations are derived and the process of selecting source terms for the adjoint neutron transport equation in order to calculate the error in a given quantity of interest (QoI) is discussed. Several numerical verification benchmark test cases are utilised to investigate how the constraint based local refinement affects the numerical accuracy and the rate of convergence of the NURBS based IGA spatial discretisation. The nuclear reactor physics verification benchmark test cases show that both AMR algorithms are superior to uniform refinement with respect to accuracy per degree of freedom. Furthermore, it is demonstrated that for global QoI the FEI driven AMR and WEI driven AMR produce similar results. However, if local QoI are desired then WEI driven AMR algorithm is more computationally efficient and accurate per degree of freedom